Tetrahydroisoquinoline papain-like protease inhibitors and their uses

Abstract

This invention relates to the field of medicinal chemistry, specifically to a tetrahydroisoquinoline papain-like protease inhibitor of formula (I) and its uses.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to the tetrahydroisoquinoline papain-like protease inhibitor shown in formula (I) and its uses. Background Technology

[0002] In the coronavirus infection mechanism, papain-like protease (PLpro) has become a key target for antiviral drug development due to its dual function—cleaving viral polymers to promote replication and interfering with the host immune response through deubiquitination and deSGylation. PLpro's catalytic domain and substrate-binding pocket are highly conserved in various coronaviruses (such as SARS-CoV-2, SARS-CoV, and HCoV-NL63), with a natural mutation frequency of only 8% of that of the spike protein, significantly reducing the risk of drug resistance. In contrast, existing anticoronavirus drugs such as remdesivir (targeting RdRp) and nematvir (targeting 3CLpro) have faced resistance mutation problems, such as the E166V mutation in 3CLpro and the V792I mutation in RdRp, which weakens their efficacy.

[0003] Existing inhibitors of PLpro fall into two categories: non-covalent and covalent inhibitors. Non-covalent inhibitors, such as GRL0617, can block substrate binding, but their in vitro inhibitory activity is weak and their inhibition of deubiquitination function is limited. While optimized compounds have improved inhibitory activity and achieved broad-spectrum inhibition, further improvements are still needed. Covalent inhibitors, such as HUP0109 and VIR-251, have some inhibitory effects, but they suffer from poor metabolic stability, potential off-target effects, and the risk of drug resistance mutations, respectively. Newly developed preclinical candidates, such as Jun12682, WEHI-P8, and HL-21, have shown certain advantages, but still face technical bottlenecks such as selectivity challenges, metabolism and toxicity, and delays in clinical translation.

[0004] In summary, research on PLpro inhibitors has moved from early target validation to the stage of rational design and clinical translation. Several candidate molecules have shown potential in preclinical trials, but no drugs have yet entered the market. Novel PLpro inhibitors are still needed to overcome bottlenecks in selectivity, drug resistance, and delivery efficiency, and to improve immune regulation, thus providing new options for coronavirus treatment. Summary of the Invention

[0005] The first aspect of the present invention provides a compound of formula (I), or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof.

[0006]

[0007]

[0008] in,

[0009] R1, R2, R3, and R4 are each independently selected from H, halogens, -CN, -OH, -COOH, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2、-NHC(=O)-C 1-6 Alkyl group, -NHC(=O)OC 1-6 Alkyl and C 3-8 cycloalkyl;

[0010] R5 is selected from H, halogen, nitro, -CN, -OH, -NH2, -COOH, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2 and C 3-8 cycloalkyl;

[0011] Cycle A is selected from 5-14 member heteroaryl groups, C 6-12 Aryl, C 6-14 Cycloalkenyl and 6-14 membered heterocyclic groups;

[0012] R6 groups are independently selected from H, halogens, nitro groups, -CN, -OH, -NH2, -COOH, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, -SC 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups and C 6-10 Aryl;

[0013] m can be 0, 1, 2, or 3.

[0014] In some implementation schemes, R1, R2, R3, and R4 are each independently selected from H, -OH, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl group, -NHC(=O)-C 1-6 Alkyl groups and -NHC(=O)OC 1-6 alkyl.

[0015] In some implementations, R1 is selected from H, -OH, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and -OC 1-4 alkyl.

[0016] In some implementations, R1 is selected from H and C. 1-4 alkyl.

[0017] In some implementations, R1 is selected from H and CH3.

[0018] In some implementations, R2 is selected from H, -OH, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and -OC 1-4 alkyl.

[0019] In some implementations, R2 is selected from H, -OH, -CH3, -CH2CH3, -CH(CH3)2, -OCH3, and -OCH2CH3.

[0020] In some implementations, R2 is selected from H, -OH, -CH3, and -OCH3.

[0021] In some implementations, R3 is selected from H, -OH, C 1-4 Alkyl, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl group, -NHC(=O)-C 1-4 Alkyl groups and -NHC(=O)OC 1-4 alkyl.

[0022] In some embodiments, R3 is selected from H, -OH, -CH3, -CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -NHCH3, -NHCH2CH3, -NHCH(CH3)2, -NHC(=O)CH3, -NHC(=O)CH2CH3, -NHC(=O)OCH3 and -NHC(=O)OC(CH3)3.

[0023] In some implementations, R3 is selected from H, -OH, -CH3, -OCH3, -NHCH3, -NHC(=O)CH3 and -NHC(=O)OC(CH3)3.

[0024] In some implementations, R4 is selected from H, -OH, and C. 1-4 alkyl.

[0025] In some implementations, R4 is H.

[0026] In some implementations, R1 is selected from H and CH3, and R2, R3, and R4 are H.

[0027] In some implementations, R2 is selected from H, OH, CH3 and OCH3, R3 is selected from H and OH, and R1 and R4 are H.

[0028] In some implementations, R3 is selected from H, OH, CH3, OCH3, NHCH3, -NHC(=O)CH3 and -NHC(=O)OC(CH3)3, and R1, R2 and R4 are H.

[0029] In some implementations, R5 is selected from H, halogens, -CN, -OH, -COOH, and C. 1-6 alkyl.

[0030] In some implementations, R5 is C 1-4 alkyl.

[0031] In some implementations, R5 is -CH3, -CH2CH3, and -CH(CH3)2.

[0032] In some implementations, R5 is -CH3.

[0033] In some implementations, ring A is selected from C. 6-10 Aryl, 5-12 heteroaryl, C 8-10 Cycloalkenyl and 8-10 membered heterocyclic groups.

[0034] In some embodiments, ring A is selected from phenyl, naphthyl, 5-12 membered heteroaryl, benzo[C] 5-6 Cycloalkenyl and benzo(5-6) heterocyclic alkenyl.

[0035] In some embodiments, ring A is selected from phenyl, naphthyl, thiophene, thiazolyl, pyrrole, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, benzopyrazolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, benzothiophene, benzothiazolyl, quinolinyl, isoquinolinyl, pyridopyrrole, pyridopyrrole, pyridopyrazolyl, dibenzothiophene, indanyl, and isoindoline-1-one.

[0036] In some implementations, ring A is selected from...

[0037] In some implementations, R6 is independently selected from H, halogens, -OH, -NH2, -COOH, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl, -NH-C 1-4Alkyl, -SC 1-4 Alkyl, 4-8 membered heterocyclic groups and phenyl.

[0038] In some embodiments, R6 is independently selected from H, F, Cl, Br, I, -OH, -CH3, -CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH(CH3)2, -SCH3, -SCH2CH3, -SCH(CH3)2, phenyl, pyrrolyl, morpholinyl, piperidinyl, and piperazine.

[0039] In some embodiments, R6 is independently selected from H, F, Cl, Br, -OH, -CH3, -CH(CH3)2, -OCH3, -SCH3, phenyl and

[0040] In some implementations, m is 0, 1, or 2.

[0041] In some implementation schemes, structural units Selected from

[0042] In some embodiments, the compound is selected from...

[0043]

[0044]

[0045]

[0046] A second aspect of the present invention provides a pharmaceutical composition comprising at least one compound described in the first aspect of the present invention, or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutical carriers and / or excipients.

[0047] The third aspect of the invention provides the use of the compounds, stereoisomers thereof, tautomers thereof, solvates thereof, isotopically labeled compounds thereof, pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the second aspect of the invention in the preparation of medicaments for treating and / or preventing diseases or conditions or reducing the severity of said diseases or conditions, said diseases or conditions being caused by coronaviruses, said medicaments including human and veterinary medicaments.

[0048] In some implementations, the disease or condition is selected from respiratory diseases (e.g., uncomplicated infections such as fever, cough and sore throat, pneumonia, acute respiratory infection, severe acute respiratory infection (SARI), hypoxic respiratory failure and acute respiratory distress syndrome, COVID-19, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS)), sepsis, septic shock and feline infectious peritonitis.

[0049] Terminology Definition

[0050] In this application, unless otherwise stated, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, to better understand this application, definitions and explanations of relevant terms are provided below.

[0051] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of the compounds of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Such salts include: salts formed by addition to inorganic acids or acids formed with organic acids, or salts in which acidic protons present on the parent compound are replaced by metal ions, or coordination compounds formed with organic bases.

[0052] Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by other methods used in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, disglucuronate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioate, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, p-pentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and similar salts.

[0053] Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and similar salts. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using the relative ions of halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0054] Pharmaceutically acceptable salts are also intended to include hemisalts, wherein the ratio of compound to acid is 2:1. Exemplary hemisalts are those derived from acids containing two carboxylic acid groups, such as malic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, glutaric acid, oxalic acid, adipic acid, and citric acid. Other exemplary hemisalts are those derived from diprotic mineral acids (e.g., sulfuric acid). Preferred exemplary hemisalts include (but are not limited to) hemi-maleic acid salts, hemi-fumaric acid salts, and hemi-succinic acid salts.

[0055] As used herein, the term "isotope-labeled compound" refers to a compound in which one or more atoms are replaced by atoms of the same number but with a different atomic mass or mass number than the dominant atomic mass or mass number found in nature. Examples of isotopes suitable for inclusion in compounds of this application include, but are not limited to, hydrogen isotopes such as... 2 H, 3 H; carbon isotopes, for example 11 C, 13 C and 14 C; Chlorine isotopes, for example 36 Cl; fluorine isotopes, for example 18 F; Iodine isotopes, for example 123 I and 125 I; nitrogen isotopes, for example 13 N and 15 N; oxygen isotopes, for example 15 O, 17 O and 18 O; and sulfur isotopes such as 35 S.

[0056] As used in this application, the term "stereoisomer" refers to an isomer formed by at least one asymmetric center. In compounds having one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers can be produced. Specific individual molecules may also exist as geometric isomers (cis / trans).

[0057] Similarly, the compounds of this application may exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0058] Unless otherwise stated, the compounds of this application may exist as stereoisomers (including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, trans-blocking isomers, and mixtures thereof). The compounds of this application may exhibit more than one type of isomerism and may consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).

[0059] The compounds of this invention may exist as solvates (such as hydrates), wherein the compounds of this application contain a solvent, such as water, methanol, or ethanol, as a structural element of the compound's crystal lattice. The amount of the solvent may be stoichiometric or non-stoichiometric.

[0060] As used in this application, the term "optionally substituted" means that the group may be unsubstituted or substituted, for example, "C..." 1-6 "Alkyl optional halogen substitution" indicates C 1-6 Alkyl groups can be unsubstituted or substituted with halogens to yield haloalkyl groups. It should be understood that when stating "R is selected from C...", the expression "R is selected from C..." is considered appropriate. 1-6 Alkyl, -OC 1-6 Alkyl and -NH-C 1-6 Alkyl, the C 1-6 When "alkyl groups are optionally substituted with halogens", it indicates that C 1-6 Alkyl, -OC 1-6 Alkyl and -NH-C 1-6 C in alkyl 1-6 Alkyl groups are optionally substituted with halogens. It should be understood that -N-(C 1-6 Alkyl)2 indicates that two carbon atoms are attached to the nitrogen atom. 1-6 Alkyl groups, which can be the same or different.

[0061] As used herein, unless otherwise expressly indicated, the descriptive phrase “...each independently selected” used throughout may mean either that the specific options expressed by the same or different symbols in different groups do not affect each other, or that the specific options expressed by the same or different symbols in the same group do not affect each other.

[0062] As used in this application, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0063] As used in this application, the term "alkyl" refers to a straight-chain or branched monovalent saturated hydrocarbon group, such as C10. 1-6 Alkyl groups refer to those having 1 to 6 carbon atoms, such as 1, 2, 3, 4, 5, or 6 carbon atoms; C 1-4 Alkyl refers to a compound having 1 to 4 carbon atoms, such as 1, 2, 3, or 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, propyl, butyl, etc.

[0064] As used in this application, the term "halogenated" refers to a modified group being substituted with one or more halogens, for example, substituted with 1, 2, 3, 4, 5, or 6 halogens. For example, "C 1-6 "Halogenated alkyl" refers to C as defined above. 1-6 The alkyl group is substituted with one or more halogens, including but not limited to CF3, CHF2, or CF2CF3.

[0065] As used herein, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of carbon atoms. For example, C 3-6 Cycloalkyl groups have 3 to 6 carbon atoms, such as 3, 4, 5, or 6 carbon atoms, wherein the C... 3-6 Cycloalkyl groups include C 4-6 cycloalkyl, C 4-5 cycloalkyl, C 3-5 Cycloalkyl groups, etc. Examples include, but are not limited to, cyclohexyl, cycloheptyl, adamantyl, etc.

[0066] As used herein, the term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group consisting of carbon atoms. For example, C 4-12 The cycloalkenyl group has 4 to 12 carbon atoms, such as 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, wherein the C 4-12 Cycloalkenyl groups include C 4-8 Cycloalkenyl, C 6-12 Cycloalkenyl, C 6-10 Cycloalkenyl, C 6-8 Cycloalkenyl groups, etc. The cycloalkenyl group includes monocyclic, bicyclic, or polycyclic rings, including spirocyclic, fused, or bridged rings. Examples include, but are not limited to, cyclohexenyl, hexahydronaphthyl, etc. wait.

[0067] As used herein, the term "heterocyclic group" refers to a saturated or partially unsaturated monovalent cyclic group composed of ring atoms, wherein 1, 2, 3, or 4 ring atoms are heteroatoms, and the remainder are carbon atoms; preferably, the heteroatoms are selected from N, O, or S, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms may optionally be oxidized. For example, a 5-12 membered heterocyclic group refers to a group composed of 5-12 ring atoms, including 5-10 membered heterocyclic groups, 5-7 membered heterocyclic groups, 4-8 membered heterocyclic groups, 4-6 membered heterocyclic groups, etc. The heterocyclic group includes monocyclic, bicyclic, or polycyclic rings, including spirocyclic, fused, or bridged rings. Examples include, but are not limited to, oxocyclic butyl, azacyclic butyl, pyrrolidinyl, piperidinyl, piperazineyl, morpholinyl, etc. wait.

[0068] As used in this application, the term "partially unsaturated" refers to a ring system that is neither saturated (i.e., does not contain double bonds) nor completely unsaturated (i.e., contains the maximum possible number of double bonds). In other words, a partially unsaturated ring system contains at least one double bond, but not the maximum possible number of double bonds.

[0069] As used in this application, the term "aryl" refers to an unsaturated group consisting of carbon atoms with a conjugated π-electron system. For example, 6-12 aryl groups consist of 6 to 12 (e.g., 6, 7, 8, 9, or 10) ring atoms, including 6-10 aryl groups. Examples include, but are not limited to, phenyl and naphthyl groups.

[0070] As used herein, the term "heteroaryl" refers to an unsaturated group consisting of ring atoms with a conjugated π-electron system, wherein 1, 2, 3, or 4 ring atoms are heteroatoms, and the remainder are carbon atoms; preferably, the heteroatoms are selected from N, O, or S, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized. For example, 5-10-membered heteroaryls consist of 5 to 10 (e.g., 5, 6, 7, 8, 9, or 10) ring atoms, including 5-9-membered, 9-10-membered, and 5-6-membered heteroaryls, etc. The heteroaryls include monocyclic and polycyclic compounds, examples of which include, but are not limited to, imidazolyl, pyridinyl, quinolinyl, or isoquinolinyl compounds.

[0071] As used herein, the term "pharmaceutical carrier and / or excipient" refers to a carrier and / or excipient that is pharmacologically and / or physiologically compatible with the subject and the active ingredient, as is well known in the art (see, for example, Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995). Pharmaceutical carriers and / or excipients include, but are not limited to: pH adjusters, surfactants, ionic strength enhancers, diluents, agents for maintaining osmotic pressure, agents for delaying absorption, preservatives, and stabilizers. For example, pH adjusters include, but are not limited to, phosphate buffers. Surfactants include, but are not limited to, cationic, anionic, or nonionic surfactants, such as Tween-80. Ionic strength enhancers include, but are not limited to, sodium chloride. Preservatives include, but are not limited to, various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc. Agents for maintaining osmotic pressure include, but are not limited to, sugars, NaCl, and their analogues. Agents for delaying absorption include, but are not limited to, monostearates and gelatin. Diluents include, but are not limited to, water, aqueous buffers (such as buffered saline), alcohols, and polyols (such as glycerol). Preservatives include, but are not limited to, various antibacterial and antifungal agents, such as thimerosal, 2-phenoxyethanol, parabens, chlorobutanol, phenol, sorbic acid, etc. Stabilizers have the meaning commonly understood by those skilled in the art for stabilizing the desired activity of the active ingredient in a pharmaceutical product, including, but not limited to, monosodium glutamate, gelatin, SPGA, sugars (such as sorbitol, mannitol, starch, sucrose, lactose, dextran, or glucose), amino acids (such as glutamic acid, glycine), proteins (such as dried whey, albumin, or casein) or their degradation products (such as lactalbumin hydrolysate), etc.

[0072] As used herein, the term "effective amount" means an amount sufficient to achieve, or at least partially achieve, the desired effect. For example, an effective amount for disease prevention means an amount sufficient to prevent, stop, or delay the onset of a disease; an effective amount for disease treatment means an amount sufficient to cure or at least partially stop the disease and its complications in a patient already suffering from the disease. Determining such an effective amount is entirely within the capabilities of those skilled in the art. For example, an effective amount for therapeutic purposes will depend on the severity of the disease to be treated, the overall state of the patient's own immune system, the patient's general characteristics such as age, weight, and sex, the method of administration of the drug, and other concurrent treatments, etc.

[0073] As used herein, the term "treatment" aims to alleviate, reduce, improve, or eliminate a targeted disease state or symptom. A subject is successfully "treated" if, in accordance with the methods described herein, a therapeutic amount of the compound, its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, its pharmaceutically acceptable salt, or the pharmaceutical composition described herein, and the subject exhibits an observable and / or detectable reduction or improvement in one or more indications and symptoms. It should also be understood that treatment of the disease state or symptom includes not only complete treatment but also the achievement of some biological or medically relevant outcome without achieving complete treatment.

[0074] As used in this application, the term "prevention" aims to avoid, reduce, prevent, or delay the onset of a disease or disease-related symptoms before the onset of the relevant drug. "Prevention" does not necessarily require the complete prevention of the onset of a disease or disease-related symptoms. For example, reducing the risk of a subject developing a specific disease or disease-related symptoms after the administration of the relevant drug, or lessening the severity of subsequently occurring related symptoms, can be considered as "prevention" of the onset or development of the disease.

[0075] Beneficial effects

[0076] This invention provides a novel papain-like protease inhibitor. The inhibitor of this invention has antiviral activity, inhibits cells infected with the novel coronavirus, and has superior stability and oral pharmacokinetic properties. Detailed Implementation

[0077] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified in the examples, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0078] General reaction route:

[0079]

[0080] Raw material A reacts with raw material B to obtain product P. The reaction reagents and conditions are provided exemplary in the reaction steps of the route, wherein R1, R2, R3, R4, R5, ring A, R6, and m are as defined in any embodiment of the present invention.

[0081] Preparation of intermediates

[0082] Intermediate B29: Synthesis of 1-(4-fluoro-1-benzofuran-7-yl)ethyl-1-one

[0083]

[0084] B29-1 (428 mg, 2.00 mmol) and B29-2 (869 mg, 2.40 mmol) were placed in a single-necked flask, and dried dioxane (8 mL), TEA (607 mg, 6.00 mmol), and Pd(PPh3)2Cl2 (140 mg, 0.2 mmol) were added. The mixture was heated to 100 °C under a nitrogen atmosphere and stirred overnight. After the reaction was complete, the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to remove the solvent, and THF (8 mL) and hydrochloric acid solution (2N, 3 mL) were added. The mixture was stirred at room temperature for 0.5 h. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (EA) (50 mL x 3). The organic phases were combined. After concentration under reduced pressure, the mixture was purified by column chromatography (PE:EA = 5:1-3:1) to obtain an oily substance B29 (214 mg, 1.20 mmol, 60%).

[0085] Synthesis of intermediate B30: 1-(3-fluoroquinolin-5-yl)ethyl-1-one

[0086]

[0087] Following the synthesis method of intermediate B29, B30 (52 mg, 0.27 mmol, 62%) was prepared by replacing B29-1 with B30-1 (100 mg, 0.44 mmol).

[0088] Synthesis of intermediate B31: 1-(dibenzo[1,2-b:1',2'-d]thiophene-4-yl)ethyl-1-one

[0089]

[0090] Following the synthesis method of intermediate B29, B31 (223 mg, 0.98 mmol, 86%) was prepared by replacing B29-1 with B31-1 (300 mg, 1.14 mmol).

[0091] Synthesis of intermediate B32: 1-[4-(methylthio)-1-benzofuran-7-yl]ethyl-1-one

[0092]

[0093] B29 (100 mg, 0.56 mmol) was placed in a single-necked flask, and DMSO (2 mL) and H2O (1 mL) were added. Finally, sodium methanethiol (78 mg, 1.12 mmol) was added, and the mixture was stirred at room temperature for 2.0 h. After the reaction was completed, water (30 mL) was added to the reaction solution, and the mixture was extracted with EA (50 mL x 3). The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 2:1-1:1) to obtain solid B32 (99 mg, 0.48 mmol, 86%).

[0094] Synthesis of intermediate B34: 1-[1-(propyl-2-yl)pyrrolo[2,3-c]pyridin-3-yl]ethyl-1-one

[0095]

[0096] B34-1 (100 mg, 0.62 mmol) was placed in a single-necked flask, DMF (2 mL) was added, the temperature was lowered to 0 °C, 2-iodopropane (127 mg, 0.75 mmol) was added, the temperature was raised to room temperature, and the reaction was stirred for 3.0 h. The reaction was then stopped. After the reaction was complete, water (30 mL) was added to the reaction solution, and the mixture was extracted with EA (50 mL x 3). The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 2:1-1:1) to obtain solid B34 (100 mg, 0.50 mmol, 80%).

[0097] Synthesis of intermediate B36: 1-(quinolin-5-yl)ethyl-1-one

[0098]

[0099] Following the synthesis method of intermediate B29, solid B36 (96 mg, 0.56 mmol, 56%) was prepared by replacing B29-1 with B36-1 (207 mg, 1.00 mmol).

[0100] Synthesis of Intermediate B37: 1-(8-chloroquinoline-5-yl)acet-1-one

[0101]

[0102] Following the synthesis method of intermediate B29, solid B37 (86 mg, 0.42 mmol, 42%) was prepared by replacing B29-1 with B37-1 (241 mg, 1.00 mmol).

[0103] Example 1: 2-(1-(naphth-1-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline-6-ol (Compound 1)

[0104]

[0105] Step 1: A1 (298 mg, 2.00 mmol) and B1 (510 mg, 3.00 mmol) were placed in a single-necked flask, and dry THF (8 mL) and Ti(OEt)4 (1369 mg, 10.11 mmol) were added. Under a nitrogen atmosphere, the mixture was heated to 80 °C and stirred overnight. The mixture was then cooled to room temperature, and NaBH4 (151 mg, 4.00 mmol) was added. The mixture was stirred for 1.0 h, and the reaction was stopped. After the reaction was complete, water (50 mL) and ethyl acetate (50 mL) were added to the reaction solution. The mixture was filtered through diatomaceous earth, and the filtrate was separated. The aqueous phase was extracted with ethyl acetate (50 mL x 2), and the organic phases were combined. After concentration under reduced pressure, the mixture was purified by column chromatography (PE:EA = 1:1 - DCM:MeOH = 20:1) to give compound 1 (194 mg, 0.64 mmol), solid, yield 35%. Ms(ESI,m\z):[M+H] + 304.15. 1 H NMR(600MHz,DMSO-d6)δ8.01(s,1H),7.95(s,1H),7.86(s,1H),7.82(s,1H),7 .51(d,J=1.8Hz,2H),7.39(s,1H),7.02(dt,J=7.5,1.0Hz,1H),6.63(dd,J=7.5 ,2.0Hz,1H),6.48(dt,J=2.0,1.0Hz,1H),3.87(d,J=1.1Hz,1H),3.83(s,1H), 3.74(d,J=0.9Hz,1H),3.03(s,1H),2.91(s,1H),2.84(dd,J=15.5,0.9Hz,2H). 13 C NMR(125MHz,DMSO-d6)δ158.43,143.88,137.73,134.60,131.06,131.04,130.95,130.67,1 30.00,129.45,129.31,129.03,128.10,116.09,115.10,64.46,62.43,51.26,30.26,21.01.

[0106] Example 2: 2-[1-(naphth-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-6,7-diol (compound 2)

[0107]

[0108] Step 1: Following the synthesis method of compound 1, compound 2-1 (243 mg, 0.70 mmol, 35%) was prepared by replacing A1 with A2 (386 mg, 2.00 mmol).

[0109] Step 2: Compound 2-1 (243 mg, 0.70 mmol) was placed in a single-necked flask, and 6 mL of dry DCM was added. The mixture was cooled to 0 °C, and BBr3 (7 mL, 7.0 mmol, 1.0 M in DCM) was added dropwise. The mixture was stirred for 2.0 h, and then the reaction was stopped. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure, and the pH was adjusted to 5-6 with saturated NaHCO3 solution. The solution was extracted with EA (30 mL x 3), and the organic phases were combined. After concentration under reduced pressure, the solution was purified by column chromatography (PE:EA = 1:1-2:1) to obtain solid compound 2 (183 mg, 0.57 mmol, 82%). Ms(ESI,m\z):[M+H] + 320.15. 1 H NMR (600MHz, DMSO-d6) δ7.95(s,1H),7.86(s,1H),7.82(s,1H),7.51(d,J=1.8Hz,2H),7.39(s,1H),7.03(s,1H),6.87(s,1H), 6.54(dt,J=2.1,1.1Hz,2H),3.88-3.81(m,2H),3.73(d,J=1.1Hz,1H),3.03(s,1H),2.91(s,1H),2.82(dd,J=15.6,0.9Hz,2H). 13 CNMR(125MHz,DMSO-d6)δ145.55,144.44,143.88,134.60,131.06,131.04,130.95,130.00,1 29.66,129.45,129.31,128.82,128.10,117.10,114.07,64.42,62.38,51.53,30.08,21.01.

[0110] Example 3: 2-[1-(naphth-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-phenol (compound 3)

[0111]

[0112] Following the synthetic method of compound 1, solid compound 3 was obtained with a yield of 31%, Ms(ESI,m\z):[M+H] + 304.16. 1H NMR (600MHz, DMSO-d6) δ7.95(s,1H),7.86(s,1H),7.81(d,J=18.0Hz,2H),7.51(d,J=1.8Hz,2H),7.39(s,1H),6.91(dt,J=7.5,1.0Hz,1 H),6.66(dd,J=7.5,2.0Hz,1H),6.54(dt,J=1.9,0.9Hz,1H),3.86-3.81(m,2H),3.72(d,J=0.9Hz,1H),3.01(s,1H),2.90-2.81(m,3H). 13 C NMR(125MHz,DMSO-d6)δ156.45,143.88,134.96,134.60,133.71,131.06,131.04,130.95,1 30.00,129.58,129.45,129.31,128.10,116.12,114.70,64.42,62.12,52.55,31.10,21.01.

[0113] Example 4: 6-(methylamino)-2-[1-(naphth-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline (compound 4)

[0114]

[0115] Step 1: Following the synthesis method of compound 1, compound 4-1 (163 mg, 0.54 mmol, 40%) was prepared by replacing A1 with A4 (200 mg, 1.35 mmol).

[0116] Step 2: Compound 4-1 (163 mg, 0.54 mmol) was placed in a single-necked flask, and dried DCM (3 mL), TEA (164 mg, 1.62 mmol), DMAP (7 mg, 0.054 mmol), and (Boc)₂O (124 mg, 0.57 mmol) were added. The mixture was stirred overnight at room temperature, and then the reaction was stopped. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (PE:EA = 3:1-1:1) to obtain solid compound 4-2 (217 mg, 0.49 mmol, 90%).

[0117] Step 3: Compound 4-2 (100 mg, 0.25 mmol) was placed in a single-necked flask, and dry THF (5 mL) and LiAlH4 (38 mg, 0.75 mmol) were added. The mixture was heated to 70 °C and stirred overnight. The reaction was then stopped. After the reaction was complete, saturated NaHCO3 solution (20 mL) and ethyl acetate (30 mL) were added to the reaction solution. The mixture was filtered through diatomaceous earth, and the filter cake was washed with EA (10 mL). The filtrate was separated, and the aqueous phase was extracted again with EA (30 mL x 2). The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 1:1 - DCM:MeOH = 20:1) to obtain solid compound 4 (57 mg, 0.18 mmol, 72%). Ms(ESI,m\z):[M+H] + 317.19. 1 H NMR(600MHz,DMSO-d6)δ7.95(s,1H),7.86(s,1H),7.82(s,1H),7.51(d,J=1 .9Hz,1H),7.39(s,1H),7.12(dt,J=7.5,1.1Hz,1H),6.73(dt,J=2.0,1.0Hz ,1H),6.61(dd,J=7.5,2.0Hz,1H),5.58(s,1H),3.87(d,J=1.1Hz,1H),3.83 (s,1H),3.74(d,J=1.0Hz,1H),3.04(s,1H),2.96(s,2H),2.93-2.84(m,3H). 13 C NMR(125MHz,DMSO-d6)δ148.43,143.88,139.90,134.60,132.91,131.06,131.04,130.95,1 30.00,129.45,129.31,128.10,113.61,112.70,64.46,62.31,51.66,31.52,29.42,21.01.

[0118] Example 5: 2-[1-(naphth-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline (compound 5)

[0119]

[0120] Following the synthetic method of compound 1, solid compound 5 was obtained in 35% yield, Ms(ESI,m\z):[M+H] + 288.16. 1H NMR (600MHz, DMSO-d6) δ7.95(s,1H),7.86(s,1H),7.82(s,1H),7.51(d,J=1.9Hz,1H),7.25-7.16(m,4H),7.12(dd dt,J=5.0,3.3,2.2,0.9Hz,1H),3.87(d,J=0.6Hz,1H),3.83(s,1H),3.74(s,1H),3.01(s,1H),2.90-2.83(m,2H). 13 C NMR(125MHz,DMSO-d6)δ143.88,139.79,138.23,134.60,131.21,131.06,131.04,130.95,1 30.91,130.02,130.00,129.45,129.31,128.96,128.10,64.46,63.25,52.54,31.23,21.01.

[0121] Example 6: {2-[1-(naphthyl-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-6-yl} tert-butyl carbamate (compound 6)

[0122]

[0123] Following the synthetic method of compound 1, solid compound 6 was obtained with a yield of 33%, Ms(ESI,m\z):[M+H] + 403.23. 1 H NMR (600MHz, DMSO-d6) δ7.95(s,1H),7.86(s,1H),7.82(s,1H),7.51(d,J=1.7Hz,1H),7.39(s,1H),7.23(dd,J=7.5,2.0Hz,1H),7.15-7.08( m,1H),7.05(dt,J=2.0,1.0Hz,1H),3.87(d,J=1.1Hz,1H),3.83(s,1H),3.74(d,J=0.9Hz,1H),3.04(s,1H),2.93-2.86(m,2H),1.42(s,2H). 13C NMR (125MHz, DMSO-d6) δ153.44,143.88,140.39,139.48,134.60,134.16,131.06,131.04,130.95,130. 00,129.45,129.31,128.10,127.27,119.33,116.98,82.02,64.46,62.31,51.63,29.55,29.53,21.01.

[0124] Example 7: 6-Methoxy-2-[1-(naphth-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline (Compound 7)

[0125]

[0126] Following the synthetic method of compound 1, solid compound 7 (83 mg, 0.26 mmol, 43%) was prepared by replacing A1 with A7 (100 mg, 0.61 mmol). Ms(ESI, m\z): [M+H] + 318.17. 1 H NMR (600MHz, DMSO-d6) δ7.95(s,1H),7.86(s,1H),7.82(s,1H),7.51(d,J=1.7Hz,2H),7.39(s,1H),7.00(dt,J=7.2,1.0Hz,1H),6.81-6. 74(m,2H),3.87(d,J=1.1Hz,1H),3.82(d,J=14.7Hz,3H),3.74(d,J=0.9Hz,1H),3.03(s,1H),2.91(s,1H),2.85(dd,J=15.6,0.9Hz,2H). 13 C NMR (125MHz, DMSO-d6) δ161.66,143.88,138.10,134.60,131.06,131.04,130.95,130.00,129. 61,129.45,129.31,129.09,128.10,113.96,113.72,64.46,62.43,56.01,51.30,30.19,21.01.

[0127] Example 8: N-{2-[1-(naphthyl-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-6-yl}acetamide (Compound 8)

[0128]

[0129] Compound 4-1 (100 mg, 0.33 mmol) was placed in a single-necked flask, and DCM (3 mL), TEA (76 mg, 0.75 mmol), and Ac₂O (38 mg, 0.38 mmol) were added. The mixture was stirred at room temperature for 3.0 h, and then the reaction was stopped. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by column chromatography (PE:EA = 3:1 - DCM:MeOH = 1:1) to give solid compound 8 (74 mg, 0.22 mmol, 86%). Ms(ESI,m\z):[M+H] + 345.18. 1 H NMR (600MHz, DMSO-d6) δ8.99(s,1H),7.95(s,1H),7.86(s,1H),7.82(s,1H),7.51(d,J=1.7Hz,2H),7.29-7.21(m,3H),7.12(d t,J=7.7,1.1Hz,1H),3.87(d,J=1.1Hz,1H),3.83(s,1H),3.74(d,J=1.0Hz,1H),3.04(s,1H),2.93-2.86(m,3H),1.42(s,2H). 13 C NMR(125MHz,DMSO-d6)δ170.27,143.88,139.35,138.43,134.60,133.73,131.06,131.04,130.95,1 30.00,129.45,129.31,128.10,127.66,118.18,117.66,64.46,62.31,51.63,29.55,24.53,21.01.

[0130] Example 9: 7-Methyl-2-[1-(naphth-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline (Compound 9)

[0131]

[0132] Following the synthetic method of compound 1, solid compound 9 (78 mg, 0.26 mmol, 38%) was prepared by replacing A1 with A9 (100 mg, 0.68 mmol). Ms(ESI, m\z): [M+H] + 345.18. 1H NMR (600MHz, DMSO-d6) δ7.95 (s, 1H), 7.86 (s, 1H), 7.82 (s, 1H), 7.51 (d, J = 1.9Hz, 1H), 7.39 (s, 1H), 7.03-6. 94(m,2H),3.93(d,J=1.0Hz,1H),3.85-3.78(m,1H),3.01(s,1H),2.90-2.81(m,2H),2.33(t,J=1.0Hz,2H). 13 C NMR (125MHz, DMSO-d6) δ143.88,139.09,136.29,134.60,134.11,131.06,131.04,130.95,130. 00,129.71,129.45,129.31,128.96,128.94,128.10,64.46,61.19,52.54,31.26,22.08,21.01.

[0133] Example 10: 6-Methyl-2-[1-(naphth-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline (Compound 10)

[0134]

[0135] Following the synthetic method of compound 1, solid compound 10 (66 mg, 0.22 mmol, 32%) was prepared by replacing A1 with A10 (100 mg, 0.68 mmol). Ms(ESI, m\z): [M+H] + 302.18. 1 H NMR (600MHz, DMSO-d6) δ7.95(s,1H),7.86(s,1H),7.82(s,1H),7.51(d,J=1.9Hz,1H),7.39(s,1H),7.07-6.99(m,2H),6.95(dt, J=1.9,1.0Hz,1H),3.87-3.81(m,2H),3.73(d,J=0.9Hz,1H),3.05(s,1H),2.93(s,1H),2.88-2.82(m,2H),2.33(t,J=1.0Hz,3H). 13C NMR (125MHz, DMSO-d6) δ143.88,139.23,138.91,135.75,134.60,131.06,131.04,130.95,130. 00,129.81,129.45,129.31,129.17,128.10,127.89,64.46,63.31,51.70,29.99,22.09,21.01.

[0136] Example 11: 8-Methyl-2-[1-(naphth-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline (Compound 11)

[0137]

[0138] Following the synthetic method of compound 1, solid compound 11 (82 mg, 0.26 mmol, 41%) was prepared by replacing A1 with A1 (100 mg, 0.68 mmol). Ms(ESI, m\z): [M+H] + 302.18. 1 H NMR (600MHz, DMSO-d6) δ7.95(s,1H),7.86(s,1H),7.82(s,1H),7.51(d,J=2.0Hz,1H),7.39(s,1H),7.10-6.99(m,2H),6.95(ddt,J =7.1,2.1,0.9Hz,1H),3.84(s,1H),3.80(s,1H),3.68(s,1H),3.05(s,1H),2.93(s,1H),2.88-2.82(m,2H),2.31(d,J=0.9Hz,3H). 13 C NMR (125MHz, DMSO-d6) δ143.88,139.18,138.29,134.60,132.87,131.06,131.04,130.95,130. 00,129.48,129.45,129.31,129.17,128.38,128.10,63.02,60.38,51.67,29.90,21.01,20.29.

[0139] Example 12: 7-Methoxy-2-[1-(naphth-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline (Compound 12)

[0140]

[0141] Following the synthetic method of compound 1, solid compound 12 (87 mg, 0.27 mmol, 45%) was prepared by replacing A1 with A12 (100 mg, 0.61 mmol). Ms(ESI, m\z): [M+H] + 318.17. 1 H NMR (600MHz, DMSO-d6) δ7.95(s,1H),7.86(s,1H),7.82(s,1H),7.51(d,J=1.7Hz,1H),7.39(s,1H),6.97(dt,J=7.6,1.0Hz,1H),6 .80(dd,J=7.5,2.0Hz,1H),6.71(dt,J=1.9,0.9Hz,1H),3.86-3.78(m,3H),3.72(d,J=1.1Hz,1H),3.01(s,1H),2.90-2.81(m,2H). 13 C NMR (125MHz, DMSO-d6) δ159.73,143.88,136.79,134.60,134.07,131.06,131.04,130.95,130. 00,129.92,129.45,129.31,128.10,114.51,113.97,64.42,62.67,56.01,52.55,31.10,21.01.

[0142] Example 13: 2-[1-(4-methoxynaphthyl-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-6-phenol (Compound 13)

[0143]

[0144] Following the synthetic method of compound 1, A13 (100 mg, 0.67 mmol) and B13 (200 mg, 1.00 mmol) were used.

[0145] Solid compound 13 (65 mg, 0.19 mmol, 29%) was prepared from the starting material. Ms(ESI, m\z): [M+H] + 334.17. 1H NMR (600MHz, DMSO-d6) δ8.02(d,J=12.3Hz,2H),7.94(s,1H),7.55(s,1H),7.44(s,1H),7.02(dt,J=7.5,1.0Hz,1H),6.95(s,1H),6.63(dd,J=7.5,2. 0Hz,1H),6.48(dt,J=2.0,1.0Hz,1H),3.87(d,J=1.1Hz,1H),3.86(s,2H), 3.80-3.72(m,2H),3.03(s,1H),2.91(s,1H),2.84(dd,J=15.6,0.9Hz,2H). 13 C NMR(125MHz,DMSO-d6)δ158.56,158.43,139.30,137.73,134.24,132.47,130.67,129.63,129.03,1 28.95,127.13,125.58,125.15,116.09,115.10,111.22,64.61,62.42,56.20,51.30,30.26,20.87.

[0146] Example 14: 2-[1-(4-fluoronaphthyl-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-6-phenol (Compound 14)

[0147]

[0148] Following the synthetic method of compound 1, solid compound 14 (99 mg, 0.31 mmol, 46%) was prepared by replacing B1 with B14 (188 mg, 1.00 mmol). Ms(ESI, m\z): [M+H] + 322.15. 1 H NMR (600MHz, DMSO-d6) δ8.01(s,1H),7.93(d,J=4.9Hz,2H),7.52(d,J=1.3Hz,2H),7.11(s,1H),7.02(dt,J=7.5,1.0Hz,1H),6.63(dd,J=7.5,2.0Hz, 1H),6.48(dt,J=2.0,1.0Hz,1H),3.87(d,J=1.1Hz,1H),3.81(s,1H),3.74 (d,J=1.0Hz,1H),3.03(s,1H),2.91(s,1H),2.84(dd,J=15.5,0.9Hz,2H). 13C NMR(125MHz,DMSO-d6)δ162.12,158.43,143.60,137.73,135.44,131.44,131.06,130.67,130.3 0,129.03,128.33,126.99,126.06,116.09,115.99,115.10,64.61,62.42,51.30,30.26,20.74.

[0149] Example 15: 2-[1-(1H-indazol-4-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-6-phenol (Compound 15)

[0150]

[0151] Following the synthetic method of compound 1, solid compound 15 (45 mg, 0.15 mmol, 23%) was prepared by replacing B1 with B15 (160 mg, 1.00 mmol). Ms(ESI, m\z): [M+H] + 294.15. 1 H NMR (600MHz, DMSO-d6) δ8.47(s,1H),8.01(s,1H),7.66(s,1H),7.35(s,1H),7.02(dt,J=7.5,1.0Hz,1H),6.63(dd,J=7.5,2.0Hz,1H),6.48 (dt,J=2.0,1.0Hz,1H),3.90(d,J=1.1Hz,1H),3.77(d,J=0.9Hz,1H),3.64(s,1H),3.03(s,1H),2.91(s,1H),2.84(dd,J=15.6,0.9Hz,2H). 13 C NMR(125MHz,DMSO-d6)δ158.43,139.20,137.73,136.80,132.36,130.67,129.03,1 27.82,126.29,122.49,117.44,116.09,115.10,62.37,61.71,51.51,30.26,20.52.

[0152] Example 16: 5-[1-(6-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-yl)ethyl]-2,3-dihydro-1H-indole-2-one (Compound 16)

[0153]

[0154] Following the synthetic method of compound 1, solid compound 16 (64 mg, 0.21 mmol, 31%) was prepared by replacing B1 with B16 (175 mg, 1.00 mmol). Ms(ESI, m\z): [M+H] + 309.15. 1 H NMR (600MHz, DMSO-d6) δ8.01(s,1H),7.43(s,1H),7.22(s,1H),7.02(dt,J=7.5,1.0Hz,1H),6.63(dd,J=7.5,2.0Hz,1H),6.48(dt,J =2.0,1.0Hz,1H),3.88(d,J=1.1Hz,1H),3.76(d,J=1.1Hz,1H),3.60(s,1H),3.45(d,J=3.8Hz,2H),3.01(s,1H),2.90-2.81(m,3H). 13 CNMR(125MHz,DMSO-d6)δ174.63,158.43,143.32,142.95,137.73,130.88,129.54,129. 03,125.24,125.19,116.09,115.12,115.10,65.14,62.79,52.41,37.52,30.26,20.87.

[0155] Example 17: 2-[1-(4-bromonaphth-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-6-phenol (Compound 17)

[0156]

[0157] Following the synthetic method of compound 1, solid compound 17 (122 mg, 0.32 mmol, 48%) was prepared by replacing B1 with B17 (248 mg, 1.00 mmol). Ms(ESI, m\z): [M+H] + 309.15. 1 H NMR (600MHz, DMSO-d6) δ8.01(s,1H),7.95(d,J=7.1Hz,2H),7.67(s,1H),7.54(d,J=4.2Hz,2H),7.02(dt,J=7.5,1.0Hz,1H),6.63(dd,J=7.5 ,2.0Hz,1H),6.48(dt,J=2.0,1.0Hz,1H),3.89-3.83(m,2H),3.74(d,J=0.9Hz,1H),3.03(s,1H),2.91(s,1H),2.84(dd,J=15.6,0.9Hz,2H).13 C NMR(125MHz,DMSO-d6)δ158.43,144.21,137.73,135.01,133.04,132.80,131.16,130.86,130.6 7,129.93,129.36,129.03,127.34,124.42,116.09,115.10,62.82,62.42,51.26,30.26,20.85.

[0158] Example 18: 2-[1-(1H-indazol-7-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-6-phenol (Compound 18)

[0159]

[0160] Following the synthetic method of compound 1, solid compound 18 (49 mg, 0.17 mmol, 25%) was prepared by replacing B1 with B18 (160 mg, 1.00 mmol). Ms(ESI, m\z): [M+H] + 294.15. 1 H NMR (600MHz, DMSO-d6) δ8.37(s,1H),8.02(d,J=11.5Hz,2H),7.45(s,1H),7.02(dt,J=7.5,1.0Hz,1H),6.63(dd,J=7.5,2.0Hz,1H) ,6.48(dt,J=2.0,1.0Hz,1H),3.92(d,J=1.1Hz,2H),3.79(d,J=0.9Hz,1H),3.03(s,1H),2.90(s,1H),2.84(dd,J=15.6,0.9Hz,2H). 13 CNMR(125MHz,DMSO-d6)δ158.43,137.73,134.73,134.44,132.01,130.67,129.03,1 28.88,128.19,126.51,124.08,116.09,115.10,63.04,60.01,51.51,30.26,21.00.

[0161] Example 19: 2-[1-(1-methylindazole-5-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-6-phenol (Compound 19)

[0162]

[0163] Following the synthetic method of compound 1, solid compound 19 (68 mg, 0.22 mmol, 33%) was prepared from A1 (100 mg, 0.67 mmol) and B19 (174 mg, 1.00 mmol) as starting materials. Ms(ESI, m\z): [M+H] + 308.39. 1 H NMR (600MHz, DMSO-d6) δ8.23(s,1H),8.01(s,1H),7.85(s,1H),7.61(s,1H),7.02(dt,J=7.5,1.0Hz,1H),6.63(dd,J=7.5,2. 0Hz,1H),6.48(dt,J=2.0,1.0Hz,1H),3.88(d,J=1.1Hz,1H),3.79-3.74(m,3H),3.65(s,1H),3.01(s,1H),2.90-2.81(m,2H). 13 C NMR (125MHz, DMSO-d6) δ158.43,142.03,139.53,137.73,132.02,130.88,129.03,128. 25,126.81,123.15,116.09,115.75,115.10,64.45,62.79,52.31,33.59,30.26,20.87.

[0164] Example 20: 2-[1-(3-bromoquinoline-5-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-6-phenol (Compound 20)

[0165]

[0166] Step 1: Compound B20-1 (200 mg, 0.80 mmol) was placed in a single-necked flask, and dry THF (5 mL), DMAP (98 mg, 0.80 mmol), and TsCl (153 mg, 0.80 mmol) were added. The mixture was stirred at room temperature for 3.0 h, and then the reaction was stopped. After the reaction was complete, the reaction solution was filtered. The filtrate was taken and cooled to -20 °C under a nitrogen atmosphere. MeMgBr (1.0 mL, 1.00 mmol, 1 M in THF) was added dropwise. After the addition was complete, the mixture was stirred at this temperature for 1.0 h, and then the reaction was stopped. After the reaction was complete, saturated NH4Cl solution (30 mL) was added to the reaction solution, and the mixture was extracted with EA (50 mL x 3). The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 2:1-1:1) to obtain compound B20 (104 mg, 0.42 mmol, 52%).

[0167] Step 2: Following the synthetic method of compound 1, solid compound 20 (163 mg, 0.54 mmol, 40%) was prepared using A1 (42 mg, 0.28 mmol) and B20 (104 mg, 0.42 mmol) as starting materials. Ms(ESI,m\z):[M+H] + 383.06. 1 HNMR (600MHz, DMSO-d6) δ8.54(s,1H),8.14(s,1H),8.02(d,J=14.2Hz,2H),7.36(s,1H),7.02(dt,J=7.5,1.0Hz,1H),6.63(dd,J=7.5,2.0Hz,1H) ,6.48(dt,J=2.0,1.0Hz,1H),3.87(d,J=1.1Hz,1H),3.79(s,1H),3.74( d,J=0.9Hz,1H),3.03(s,1H),2.91(s,1H),2.84(dd,J=15.6,0.9Hz,2H). 13 C NMR(125MHz,DMSO-d6)δ158.43,150.46,147.43,139.26,137.73,132.01,131.19,130.67,1 29.20,129.03,128.57,128.54,117.75,116.09,115.10,62.87,62.37,51.29,30.26,20.47.

[0168] Example 21: 2-[1-(1-benzofuran-5-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-6-phenol (Compound 21)

[0169]

[0170] Using compound B21-1 (200 mg, 1.23 mmol) as a starting material, and following the synthetic methods of compounds B20 and 1, solid compound 21 (63 mg, 0.21 mmol) was prepared. Ms(ESI,m\z):[M+H] + 294.14. 1H NMR (600MHz, DMSO-d6) δ8.01(s,2H),7.88(s,3H),7.74(s,3H),7.15(s,2H),7.02(dt,J=7.5,1.0Hz,3H),6.95(s,2H),6.63(dd,J=7.5,2.0Hz,3H ),6.48(dt,J=2.0,1.0Hz,3H),3.88(d,J=1.1Hz,3H),3.76(d,J=1.1Hz, 3H), 3.67 (s, 2H), 3.01 (s, 2H), 2.90-2.84 (m, 5H), 2.83 (d, J = 0.9Hz, 3H). 13 C NMR(125MHz,DMSO-d6)δ158.43,157.49,147.95,141.29,137.73,130.88,129.03,128.6 4,128.11,125.93,116.09,115.10,113.31,109.03,64.34,62.79,52.31,30.26,20.87.

[0171] Example 22: 2-[1-(7-hydroxy-2,3-dihydro-1H-inden-4-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-6-phenol (Compound 22)

[0172]

[0173] Following the synthetic method of compound 1, solid compound 22 (84 mg, 0.27 mmol, 48%) was prepared by replacing B1 with B22 (100 mg, 0.57 mmol). Ms(ESI, m\z): [M+H] + 310.17. 1 H NMR (600MHz, DMSO-d6) δ8.01 (s, 1H), 7.04-6.95 (m, 2H), 6.69-6.60 (m, 2H), 6.48 (dt, J = 2.0, 1.0Hz, 1H), 5. 40(s,1H),3.87(d,J=1.1Hz,1H),3.74(dd,J=3.4,1.0Hz,2H),3.03(s,1H),2.92-2.79(m,6H),1.34(s,2H). 13C NMR(125MHz,DMSO-d6)δ158.43,155.52,138.63,137.73,136.68,130.67,129.53,129.03, 128.72,116.09,115.10,113.83,62.93,62.42,51.48,33.96,30.26,27.68,27.44,20.93.

[0174] Example 23: 2-[1-(1H-indol-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-6-phenol (compound 23)

[0175]

[0176] Following the synthetic method of compound 1, solid compound 23 was obtained in 35% yield, Ms(ESI,m\z):[M+H] + 293.15. 1 H NMR(600MHz,DMSO-d6)δ8.23(s,1H),8.01(s,1H),7.72(s,1H),7.42(s,1H) ,7.32(s,1H),7.02(dt,J=7.5,1.0Hz,1H),6.63(dd,J=7.5,2.0Hz,1H),6.48 (dt,J=2.0,1.0Hz,1H),6.38(s,1H),4.22(s,1H),3.85(d,J=0.9Hz,1H),3. 72(d,J=1.1Hz,1H),3.07(s,1H),2.94(s,1H),2.84(dd,J=15.6,0.9Hz,2H). 13 C NMR(125MHz,DMSO-d6)δ158.43,143.63,138.27,137.73,130.85,129.03,128.83,127.1 6,126.86,125.34,116.09,115.10,114.08,104.20,62.52,59.96,51.96,30.26,18.86.

[0177] Example 24: 2-[1-(isoquinoline-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-6-phenol (Compound 24)

[0178]

[0179] Following the synthetic method of compound 1, solid compound 24 (59 mg, 0.19 mmol, 33%) was prepared by replacing B1 with B24 (100 mg, 0.58 mmol). Ms(ESI, m\z): [M+H] + 305.15. 1 H NMR(600MHz,DMSO-d6)δ8.52(s,2H),8.01(s,2H),7.96(s,2H),7.78(s,2H) ,7.60(s,2H),7.53(s,2H),7.02(dt,J=7.5,1.0Hz,2H),6.63(dd,J=7.5,2.0 Hz,2H),6.48(dt,J=2.0,1.0Hz,2H),4.53(s,2H),3.89(d,J=1.1Hz,2H),3. 77(d,J=1.0Hz,2H),3.10(s,2H),2.97(s,2H),2.84(dd,J=15.6,0.9Hz,4H). 13 C NMR(125MHz,DMSO-d6)δ158.43,148.92,144.29,137.90,137.77,132.99,131.38,129.03,1 28.18,127.71,127.14,126.68,121.35,116.09,115.10,60.83,59.40,52.28,29.94,19.29.

[0180] Example 25: 2-{1-[3-(1,4-oxazacyclohexane-4-yl)phenyl]ethyl}-1,2,3,4-tetrahydroisoquinoline-6-phenol (Compound 25)

[0181]

[0182] Following the synthetic method of compound 1, solid compound 25 (92 mg, 0.27 mmol, 56%) was prepared by replacing B1 with B25 (100 mg, 0.49 mmol). Ms(ESI, m\z): [M+H] + 339.19. 1H NMR(600MHz,DMSO-d6)δ8.01(s,1H),7.23-7.13(m,1H),7.02(dt,J=7.5,1.0Hz,1H) ,6.86(dt,J=7.3,2.1Hz,1H),6.79(td,J=2.0,1.0Hz,1H),6.63(dd,J=7.5,2.0Hz,1 H),6.48(dt,J=2.0,1.0Hz,1H),3.88(d,J=1.1Hz,1H),3.76(d,J=1.1Hz,1H),3.70( s,2H),3.66(t,J=0.9Hz,1H),3.48(d,J=0.9Hz,2H),3.01(s,1H),2.90-2.81(m,2H). 13 C NMR (125MHz, DMSO-d6) δ158.43,150.12,144.06,137.73,131.18,130.88,129.03,126. 60,118.51,116.18,116.09,115.10,72.00,64.53,63.92,62.79,52.23,30.26,21.23.

[0183] Example 26: 2-[1-(benzo[d][1,3]oxazol-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-6-phenol (Compound 26)

[0184]

[0185] Following the synthetic method of compound 1, solid compound 26 (47 mg, 0.16 mmol, 26%) was prepared by replacing B1 with B26 (100 mg, 0.62 mmol). Ms(ESI, m\z): [M+H] + 295.13. 1 H NMR (600MHz, DMSO-d6) δ8.01(s,2H),7.82(s,2H),7.52(s,2H),7.43(s,2H),7.02(dt,J=7.5,1.0Hz,2H),6.63(dd,J=7.5,2.0Hz,2H),6.48 (dt,J=2.0,1.0Hz,2H),4.30(s,2H),3.91(d,J=1.1Hz,2H),3.78(d,J=1.1Hz,2H),3.16(s,2H),3.04(s,2H),2.84(dd,J=15.6,1.0Hz,4H). 13C NMR(125MHz,DMSO-d6)δ159.66,158.46,152.26,141.31,137.40,135.09,129.03,1 28.70,127.58,121.56,116.09,115.10,113.42,64.38,63.01,52.51,30.77,18.72.

[0186] Example 27: 2-[1-(1H-indol-4-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-6-phenol (compound 27)

[0187]

[0188] Following the synthetic method of compound 1, solid compound 27 (53 mg, 0.18 mmol, 29%) was prepared by replacing B1 with B27 (100 mg, 0.63 mmol). Ms(ESI, m\z): [M+H] + 293.15. 1 H NMR (600MHz, DMSO-d6) δ9.01(s,1H),8.01(s,1H),7.41(s,1H),7.19(d,J=2.1Hz,2H),7.02(dt,J=7.5,1.0Hz,1H),6.63(dd,J=7.5,2.0Hz,1H),6.48( dt,J=2.0,1.0Hz,1H),6.42(s,1H),3.87(d,J=1.1Hz,1H),3.79(s,1H),3.7 4(d,J=0.9Hz,1H),3.03(s,1H),2.91(s,1H),2.84(dd,J=15.6,0.9Hz,2H). 13 C NMR(125MHz,DMSO-d6)δ158.43,141.74,138.12,137.73,130.67,129.03,127.48,127.2 9,126.84,126.35,116.09,115.10,114.22,104.69,62.42,61.60,51.29,30.26,20.46.

[0189] Example 28: 2-[1-(2,3-dihydro-1H-inden-5-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-6-phenol (Compound 28)

[0190]

[0191] Following the synthetic method of compound 1, solid compound 28 (106 mg, 0.36 mmol, 58%) was prepared by replacing B1 with B28 (100 mg, 0.63 mmol). Ms(ESI, m\z): [M+H] + 294.17. 1 H NMR(600MHz, DMSO-d6)δ8.01(s,1H),7.23-7.17(m,1H),7.14(ddt,J=4.3,2.3,1.1Hz,1H),7.02(dt,J=7.5,1.0Hz,1H),6.63(dd,J=7.5,2.0Hz,1 H),6.48(dt,J=2.1,1.1Hz,1H),3.88(d,J=1.1Hz,1H),3.76(d,J=1.1Hz, 1H), 3.56 (t, J = 1.0Hz, 1H), 3.01 (s, 1H), 2.90-2.79 (m, 5H), 2.05 (s, 1H). 13 C NMR(125MHz,DMSO-d6)δ158.43,145.11,145.05,143.02,137.73,130.88,129.67,129.03, 128.11,127.57,116.09,115.10,65.70,62.79,52.45,34.32,33.65,30.26,28.17,20.58.

[0192] Example 29: 2-[1-(4-fluoro-1-benzofuran-7-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-6-phenol (Compound 29)

[0193]

[0194] Following the synthetic method of compound 1, solid compound 29 (73 mg, 0.36 mmol, 42%) was prepared by replacing B1 with B29 (100 mg, 0.56 mmol). Ms(ESI, m\z): [M+H] + 312.13. 1H NMR (600MHz, DMSO-d6) δ8.01(s,1H),7.87(s,1H),7.16(s,1H),7.02(dt,J=7.5,1.0Hz,1H),6.63(dd,J=7.5,2.0Hz,1H),6. 48(dt,J=2.0,1.0Hz,1H),3.87(d,J=0.9Hz,1H),3.78-3.73(m,2H),3.05(s,1H),2.92(s,1H),2.84(dd,J=15.6,0.9Hz,2H). 13 C NMR(125MHz,DMSO-d6)δ164.05,158.43,155.81,147.42,137.73,130.77,130.38,130.2 7,129.03,116.78,116.66,116.09,115.10,108.15,62.79,57.10,51.65,30.26,21.61.

[0195] Example 30: 2-[1-(3-fluoroquinoline-5-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-6-phenol (Compound 30)

[0196]

[0197] Following the synthetic method of compound 1, solid compound 30 (33 mg, 0.10 mmol, 37%) was prepared by replacing B1 with B30 (52 mg, 0.28 mmol). Ms(ESI, m\z): [M+H] + 323.14. 1 H NMR (600MHz, DMSO-d6) δ8.32(s,1H),8.02(d,J=6.3Hz,2H),7.69(s,1H),7.36(s,1H),7.02(dt,J=7.5,1.0Hz,1H),6.63(dd,J=7.5,2.0Hz,1H), 6.48(dt,J=2.0,1.0Hz,1H),3.87(d,J=1.1Hz,1H),3.83(s,1H),3.74(d,J=0.9Hz,1H),3.03(s,1H),2.91(s,1H),2.84(dd,J=15.6,0.9Hz,2H). 13C NMR(125MHz,DMSO-d6)δ158.96,158.43,147.04,139.01,137.73,137.23,131.20,130.67,1 30.30,129.24,129.03,128.85,116.09,115.73,115.10,62.42,62.37,51.29,30.26,20.49.

[0198] Example 31: 2-[1-(dibenzo[1,2-b:1',2'-d]thiophene-4-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-6-phenol (compound 31)

[0199]

[0200] Following the synthetic method of compound 1, solid compound 31 (83 mg, 0.23 mmol, 52%) was prepared by replacing B1 with B31 (100 mg, 0.44 mmol). Ms(ESI, m\z): [M+H] + 360.13. 1 H NMR (600MHz, DMSO-d6) δ8.21(d,J=11.0Hz,2H),8.01(s,1H),7.90(s,1H),7.53-7.48(m,3H),7.02(dt,J=7.5,1.0Hz,1H),6.63(dd,J=7.5, 2.0Hz,1H),6.48(dt,J=2.0,1.0Hz,1H),3.92-3.87(m,2H),3.77(d,J=0.9Hz,1H),3.03(s,1H),2.91(s,1H),2.84(dd,J=15.6,0.9Hz,2H). 13 C NMR (125MHz, DMSO-d6) δ158.43,141.55,139.90,138.44,137.73,136.72,136.37,130.67,130.37,129.6 1,129.15,129.03,126.14,124.68,124.38,124.27,116.09,115.10,62.37,57.79,51.51,30.26,20.56.

[0201] Example 32: 2-{1-[4-(methylthio)-1-benzofuran-7-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-6-phenol (Compound 32)

[0202]

[0203] Following the synthetic method of compound 1, solid compound 32 (60 mg, 0.18 mmol, 37%) was prepared by replacing B1 with B32 (99 mg, 0.48 mmol). Ms(ESI, m\z): [M+H] + 340.12. 1 H NMR (600MHz, DMSO-d6) δ8.01(s,1H),7.88(s,1H),7.46(s,1H),7.02(dt,J=7.5,1.0Hz,1H),6.93(s,1H),6.63(dd,J=7.5,2.0Hz,1H),6.48 (dt,J=2.0,1.0Hz,1H),3.87(d,J=0.9Hz,1H),3.74(d,J=1.2Hz,2H),3.05(s,1H),2.92(s,1H),2.84(dd,J=15.6,0.9Hz,2H),2.53(s,3H). 13 C NMR(125MHz,DMSO-d6)δ158.43,154.53,145.12,139.34,137.73,132.97,130.77,129.29,1 29.03,127.42,124.61,116.09,115.10,106.62,62.79,57.06,51.65,30.26,21.62,17.18.

[0204] Example 33: 2-[1-(2,3-dihydro-1H-inden-4-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-6-phenol (compound 33)

[0205]

[0206] Following the synthetic method of compound 1, solid compound 33 (110 mg, 0.37 mmol, 60%) was prepared by replacing B1 with B33 (100 mg, 0.62 mmol). Ms(ESI, m\z): [M+H] + 294.17. 1 H NMR (600MHz, DMSO-d6) δ8.01(s,1H),7.24-7.16(m,2H),7.06-6.99(m,2H),6.63(dd,J=7.5,2.0Hz,1H),6.48(dt,J=2.0, 1.0Hz,1H),3.87(d,J=1.1Hz,1H),3.75(dd,J=4.9,1.0Hz,2H),3.03(s,1H),2.93-2.79(m,6H),2.05(s,1H),1.34(s,2H).13 C NMR(125MHz,DMSO-d6)δ158.43,144.64,142.33,140.15,137.73,130.67,129.14,129.03, 127.79,127.54,116.09,115.10,62.42,60.52,51.56,33.65,33.10,30.26,27.23,20.94.

[0207] Example 34: 2-{1-[1-(prop-2-yl)pyrrolo[2,3-c]pyridin-3-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-6-phenol (Compound 34)

[0208]

[0209] Following the synthetic method of compound 1, solid compound 34 (33 mg, 0.10 mmol, 20%) was prepared by replacing B1 with B34 (100 mg, 0.50 mmol). Ms(ESI, m\z): [M+H] + 336.19. 1 H NMR (600MHz, DMSO-d6) δ8.87(s,1H),8.66(s,1H),8.01(s,1H),7.66(s,1H),7.02(dt,J=7.5,1.0Hz,1H),6.63(dd,J=7.5,2.0Hz,1H),6.48(dt,J=2. 0,1.0Hz,1H),4.57(s,1H),3.92(d,J=0.9Hz,1H),3.83-3.77(m,2H),3.03 (s,1H),2.90(s,1H),2.84(dd,J=15.6,0.9Hz,2H),1.41(d,J=11.0Hz,5H). 13 C NMR(125MHz,DMSO-d6)δ158.43,147.52,139.16,137.73,132.49,131.91,131.33,130.67, 129.03,124.25,117.54,116.09,115.10,63.04,57.10,52.62,51.51,30.26,24.74,20.01.

[0210] Example 35: 2-[1-(2-methyl-5-phenylthiophene-3-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-6-phenol (Compound 35)

[0211]

[0212] Following the synthetic method of compound 1, solid compound 35 (42 mg, 0.12 mmol, 26%) was prepared by replacing B1 with B35 (100 mg, 0.46 mmol). Ms(ESI, m\z): [M+H] + 350.15. 1 H NMR(600MHz,DMSO-d6)δ8.01(s,1H),7.90-7.83(m,2H),7.46-7.38(m,4H),7.02(dt,J=7.5,1.0Hz,1H),6.63(dd,J=7.5,2.0Hz,1H),6.4 8(dt,J=2.0,1.0Hz,1H),3.90(d,J=1.1Hz,1H),3.79-3.72(m,2H),3.03(s,1H),2.91(s,1H),2.84(dd,J=15.6,0.9Hz,2H),2.34(s,3H). 13 C NMR(125MHz,DMSO-d6)δ158.43,139.31,139.26,137.87,137.73,133.44,132.65,132.18,1 30.67,129.40,129.03,127.21,116.09,115.10,62.37,56.11,51.29,30.26,19.85,15.65.

[0213] Example 36: 2-[1-(quinolin-5-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-6-phenol (Compound 36)

[0214]

[0215] Following the synthetic method of compound 1, solid compound 36 (51 mg, 0.17 mmol, 30%) was prepared by replacing B1 with B36 (96 mg, 0.56 mmol). Ms(ESI, m\z): [M+H] + 305.15. 1H NMR (600MHz, DMSO-d6) δ8.82(s,1H),8.16(s,1H),8.02(d,J=13.0Hz,2H),7.48(s,1H),7.36(s,1H),7.02(dt,J=7.5,1.0Hz,1H),6.63(dd,J=7 .5,2.0Hz,1H),6.48(dt,J=2.0,1.0Hz,1H),3.87(d,J=1.1Hz,1H),3.77-3.72(m,2H),3.03(s,1H),2.91(s,1H),2.84(dd,J=15.6,0.9Hz,2H). 13 C NMR(125MHz,DMSO-d6)δ158.43,152.52,149.73,140.53,137.73,135.66,131.10,130.67,1 29.03,128.35,127.66,127.30,123.67,116.09,115.10,63.39,62.42,51.29,30.26,20.33.

[0216] Example 37: 2-[1-(5-chloroquinoline-8-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-6-phenol (Compound 37)

[0217]

[0218] Following the synthetic method of compound 1, solid compound 37 (31 mg, 0.092 mmol, 22%) was prepared by replacing B1 with B37 (86 mg, 0.42 mmol). Ms(ESI, m\z): [M+H] + 339.11. 1 H NMR (600MHz, DMSO-d6) δ8.83(s,1H),8.23(s,1H),8.01(s,1H),7.51(s,1H),7.46(s,1H),7.02(dt,J=7.5,1.0Hz,1H),6.63(dd,J=7.5,2 .0Hz,1H),6.48(dt,J=2.0,1.0Hz,1H),3.94-3.89(m,2H),3.79(d,J=0.9Hz,1H),3.03(s,1H),2.90(s,1H),2.84(dd,J=15.6,0.9Hz,2H). 13C NMR(125MHz,DMSO-d6)δ158.43,150.27,144.83,137.89,137.73,136.75,134.72,131.80,1 30.67,129.52,129.03,128.29,124.57,116.09,115.10,63.04,57.28,51.51,30.26,20.85.

[0219] Example 38: 2-[1-(1H-indol-7-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-6-phenol (Compound 38)

[0220]

[0221] Following the synthetic method of compound 1, solid compound 38 (48 mg, 0.16 mmol, 26%) was prepared by replacing B1 with B38 (100 mg, 0.63 mmol).

[0222] Test Example 1. Protein Level Enzyme Activity Test

[0223] The labeled peptide Z-RLRGG-AMC (GLPBIO, GA23715) was used as the substrate. The enzyme activity of PLpro was measured in black 384-well plates (GREINER, 784076) at excitation and emission wavelengths of 340 nm and 460 nm, respectively. The assay buffer contained 50 mM HEPES, 10 mM DTT, 0.1 mM EDTA, and 0.005% Tween 20 at pH 7.2. GRL0617 (TargetMol, Shanghai, China) was used as a positive control. Serially diluted compounds were added to PLpro solutions diluted with assay buffer and incubated for 10 minutes. Subsequently, the substrate peptide diluted with assay buffer was added to a mixture of PLpro and inhibitor and incubated at 37°C for 1 hour. The final concentrations of PLpro and substrate were 10 nM and 20 μM, respectively. Fluorescence intensity was monitored using a BioTek Neo2 multimode microplate reader (Agilent). The dose-inhibition curves were plotted using nonlinear regression, and the half-maximal inhibitory concentration (IC50) of the inhibitory compounds was determined using GraphPad Prism 9.0. The results are shown in Table 1.

[0224] Table 1. Inhibitory activity of compounds against PLpro

[0225]

[0226]

[0227] Note: +++ indicates 100μM≤IC 50<1000μM; ++ indicates 10μM≤IC 50 <100μM; + indicates 1μM≤IC 50 <10μM.

[0228] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them; although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications can still be made to the specific implementation of the present invention or equivalent substitutions can be made to some technical features without departing from the spirit of the technical solutions of the present invention, and all such modifications and substitutions should be covered within the scope of the technical solutions claimed in the present invention.

Claims

1. The following compounds or their pharmaceutically acceptable salts, 。 2. A pharmaceutical composition comprising at least one compound of claim 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutical carriers and / or excipients.

3. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 2 in the preparation of a medicament for treating and / or preventing a disease or condition caused by a coronavirus, wherein the medicament comprises human and veterinary medicines.

4. The use as described in claim 3, wherein, The disease or condition mentioned is selected from respiratory diseases and feline infectious peritonitis.

5. The use as described in claim 4, wherein, The respiratory illness is a simple infection.

6. The use as described in claim 5, wherein, The uncomplicated infection is selected from fever, cough, and sore throat.

7. The use as described in claim 4, wherein, The respiratory illness is pneumonia.

8. The use as described in claim 4, wherein, The respiratory illness is an acute respiratory infection.

9. The use as described in claim 4, wherein, The respiratory illness is a severe acute respiratory infection.

10. The use as described in claim 4, wherein, The respiratory diseases mentioned are selected from hypoxic respiratory failure, acute respiratory distress syndrome, COVID-19, severe acute respiratory syndrome, and Middle East respiratory syndrome.

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